Approximately 10% of patients with acute pancreatitis die from uncontrolled pancreatic inflammation that results in massive fluid losses and shock. The regulation of pancreatic inflammation is poorly understood. In the trachea, sensory nerves regulate inflammation by releasing tachykinins that bind to endothelial cells and induce arteriolar vasodilatation, plasma extravasation and neutrophil infiltration. This well-characterized phenomenon is called neurogenic inflammation. The general hypothesis of this proposal is that neurogenic mechanisms are essential to the pathogenesis of acute pancreatitis. Specifically, we hypothesize that a) tachykinins induce plasma extravasation and neutrophil infiltration in the pancreas by interacting with neurokinin receptors, b) the pro-inflammatory effects of tachykinins are terminated by cell surface peptidases, and c) tachykinins and their receptors regulate inflammation in a widely-used model of acute pancreatitis. Due to the recent availability of "knockout" mice in which the genes encoding neurokinin receptors or cell surface peptidases have been deleted by homologous recombination, these experiments will be performed in mice. Pancreatic inflammation will be assessed by 1) quantifying and localizing plasma extravasation using Evans blue and Monastral blue, respectively, 2) identifying and measuring endothelial cell gaps through which plasma extravasates using a silver stain and light microscopy, 3) quantifying and localizing neutrophil infiltration using myeloperoxidase, and 4) defining the extent of edema, and cytoplasmic vacuolization using histological criteria. Specific Aim 1 will define the contribution of exogenous and endogenous tachykinins to the initiation of acute pancreatic inflammation. The time-course and dose-response will be determined, and the neurokinin receptors that mediate these effects will be identified using antagonists and knockout mice, and localized using receptor-specific antisera. Specific Aim 2 will examine the role of peptidases in the termination of tachykinin-induced pancreatic inflammation. The peptidases neutral endopeptidase and angiotensin converting enzyme will be localized in the pancreas using specific antisera, and their importance in tachykinin-induced inflammation will be determined using inhibitors and knockout mice. Specific Aim 3 will define the importance of sensory nerves, and specifically tachykinins, in the pathogenesis of acute pancreatitis. Using neurokinin receptor antagonists, peptidase inhibitors, and knockout mice, we will delineate the neurogenic mechanisms that regulate inflammation in acute pancreatitis.